2,4,5-Trimethoxyphenethylamine

SYNTHESIS: To a solution of 39.2 g 2,4,5-trimethoxybenzaldehyde in 160
mL nitromethane there was added 7.0 g anhydrousammoniumacetate, and
the mixture was heated on the steam bath for 2 h. The
excesssolvent/reagent was removed under vacuum, leaving a deeply
colored residue that spontaneously crystallized. This was
mechanically removed and triturated under 60 mL cold MeOH.
Filtration, washing with cold MeOH and air drying, gave 49.3 g of
bright orange crystals. Trial recrystallizations from EtOAc gave a mp
of 132-133 °C; from CH3CN, 130.5-131.5 °C. The entire product was
recrystallized from 1.1 L boiling IPA to provide, after filtration,
IPA washing, and air drying, 34.5 g of beta-nitro-2,4,5-trimethoxystyrene
as yum-yum orange crystals with a mp of 132-133 °C. Literature values
are usual one-degree ranges, anywhere in the area of 127-130 °C.

To a suspension of 30 g powdered LAH in 800 mL of well stirred and
refluxing anhydrous THF there was added a solution of 34.9 g
beta-nitro-2,4,5-trimethoxystyrene in 200 mL anhydrous THF. The mixture
was maintained at reflux for an additional 36 h, cooled, and the
excess hydride activity destroyed by the addition of 30 mL H2O
followed by 30 mL 15% NaOH, and finally with another 90 mL H2O. The
solids were removed by filtration, washed with THF, and the pooled
mother liquor and washings stripped of solvent under vacuum. The
residue was dissolved in CH2Cl2, washed with both 5% NaOH and then
H2O, removing much of the color. It was then extracted with 3x75 mL N
HCl. The pooled red-colored acid extracts were washed with CH2Cl2,
made basic with 25% NaOH, and extracted with 3x75 mL CH2Cl2. Removal
of the solvent gave some 25 g of residue which was dissolved in 100 mL
IPA and neutralized with concentrated HCl. The crystalline mass that
formed was diluted with an equal volume of Et2O, and the solids
removed by filtration. Washing with cold IPA, followed by Et2O and
air drying, gave 17.7 g of 2,4,5-trimethoxyphenethylaminehydrochloride (TMPEA) as a white product. The reported melting point
was 187-188 °C.

DOSAGE: greater than 300 mg.

DURATION: unknown.

QUALITATIVE COMMENTS: (with less than 300 mg) Since it was not easy,
however, to judge the extent of a 'Rausch'-action from experiments on
animals, some injections of beta-2,4,5-trimethoxyphenethylamine were
administered to the author, and finally a control test was carried out
with an equal quantity of mescaline. The action of both these
substances in these experiments agreed only to a limited extent with
the effects described for mescaline by, for example, Beringer. It
must be remembered, however, in this connection, that the quantities
used by Beringer were larger than the doses administered in these
experiments. Nevertheless, it may be concluded that the
pharmacological action of beta-2,4,5-trimethoxyphenethylamine agrees
to a large extent with that of mescaline. However, the new compound
had more unpleasant secondary effects (nausea) and did not bring about
the euphoristic state caused by mescaline.

(with 300 mg) Under double blind conditions, I was unable to
distinguish this from a placebo. Both were without any of the changes
described after the ingestion of psychotomimetic drugs.

(with 200 mg, followed after 45 minutes, with 100 mg mescaline) RThe
normally modest effects known to be due to mescaline alone at this
level, were strongly potentiated with the earlier taking of
2,4,5-TMPEA. The effects were stronger as well as longer lived.

EXTENSIONS AND COMMENTARY: The code letters used for this drug are not
as ambiguous as they might seem at first glance. A large number of
the 2-carbonhomologues are given names based on the code for the
3-carbon compound. On that basis, this should be 2C-TMA-2, since it
is the 2-carbon counterpart of TMA-2. But since the first of the
trimethoxyphenethylamines already had a trivial name, mescaline, the
code TMPEA was unassigned. So, here is the logical place to use it.

There have been just two reports published of self-experimentation
with TMPEA, and these comments are taken from them.

The first is presented here, word for word, as it was originally
published (this was in 1931). It leaves much to be desired. The
administration was by injection (intramuscular injection?). The dose
was not given, but it was less than those reported by Beringer in his
studies with mescaline, and this latter experimenter's published
levels were all between 300 and 500 milligrams. What can one conclude
from all this? Only that TMPEA apparently did not measure up to
mescaline in his comparisons.

The second, reported some 40 years later, is not really contradictory.
Here the TMPEA was administered orally, and the subject surrounded
himself with a battery of psychological tests. This might allow
statistics to provide an aura of validity to the observations. But
the comments are pretty self-explanatory. The drug was not active in
its own right, but when employed preliminary to mescaline, greatly
enhanced the effects of the latter.

This is an area of research that deserves more attention. The simple
compound that results from the stripping of all three of the O-methyl
groups from TMPEA is the extremely potent neurotoxin,
6-hydroxydopamine. When it is ad-ministered to an otherwise intact
experimental animal, it produces sympathectomy, effectively destroying
the sympathetic nervous system. And some of the methyl groups of
TMPEA are known to be stripped off through the normal metabolic
processes that occur in the liver. There are many fascinating
psychedelics that have a signature of methoxyl groups para to
one-another. It is known that they, too, can lose a methyl group or
two. It would be intriguing to see if there was some biochemical
overlap between the metabolism of some of these centrally active drugs
and the metabolic fate of 6-hydroxydopamine. But in a test animal, of
course, rather than in man.